This Program Project renewal application outlines a group of studies investigating one of the important and intriguing complications of human immunodeficiency virus type one (HIV-1) infection, the AIDS dementia complex (ADC), a condition manifesting as a subcortical dementia with characteristic cognitive, motor and behavioral symptoms and signs. While considered to most likely result from a fundamental effect of HIV- 1, itself, rather than from another, opportunistic infection, its pathogenesis is still far from clearly understood. Central questions remain regarding the nature of brain dysfunction with its characteristic profile of psychomotor slowing and reduced attention and concentration as well as regarding its viral pathogenesis. With respect to how HIV-1 injures the brain, speculation has turned to invoke indirect mechanisms involving neurotoxins rather than direct viral cytolysis. The Program exploring these issues is organized into a Core and 4 Projects: The Core will support maintenance of a well-characterized group of HIV-1 infected subjects, a data management unit, a repository for clinical CSF and blood specimens, and a pathological specimen library. Project 6 will explore new modes of evaluating the cerebral dysfunction of ADC, focusing on continuous performance assessment and its relation to other neuropsychological, electrophysiological and metabolic (PET) measures of ADC severity. Project 4 uses quantitative metabolic (positron emission tomography, PET) and anatomic (magnetic resonance imaging, MRI) measures to study the pathophysiology and potential reversibility of ADC. Project 7 uses the emerging technology combining polymerase chain reaction (PCR)-based nucleic acid amplification methods with in situ hybridization to define the types of cells in the CNS that harbor HIV-1 genomes and to determine the kind and relative abundance of viral and cellular transcripts in infected and uninfected brain cells. Project 8 addresses the putative neurotoxic role of the viral envelope glycoprotein, gp120, by development of transgenic mouse models using cell-specific promoters to control the brain cell type secreting gp120. It also uses in vitro models of neuronal toxicity to explore whether gp120 from different viral isolates varies with respect to neurotoxicity.